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Nude Rats & Mice in Pharma: Advantages and Uses

The utilization of animal models is paramount to understanding complex human diseases and developing innovative therapies. Among these animal models, nude rats, also known as athymic nude rats, have emerged as invaluable assets in various facets of scientific inquiry. Their unique immunodeficient characteristics make them an ideal choice for a wide range of studies, from cancer research to transplantation studies. In this comprehensive exploration, we examine the applications and advantages of nude rats in pharmaceutical research and drug testing, their role in studying human diseases, and their contributions to personalized medicine.

Immunodeficient Nude Rats: A Valuable Model for Studying Human Diseases

Brief History of Humanized Rats

The history of humanized rats, particularly athymic nude rats, is a remarkable journey through the realms of immunology and biomedical research. The story begins in the early 1960s when researchers at the Rowett Research Institute in Aberdeen, Scotland, discovered a unique rat strain characterized by its lack of a thymus gland, a vital organ in the immune system. These rats were appropriately named “nude rats” due to their hairless appearance. This groundbreaking discovery opened new avenues in immunology, as it allowed scientists to create experimental models devoid of functional immune systems, paving the way for the study of human diseases, transplantation, and tumor biology. Over the decades, advances in genetic engineering and the development of specialized nude rat variants, such as RNU and SRG rats, have further expanded their utility in research. Today, humanized rats continue to play a pivotal role in advancing our understanding of diseases and developing innovative therapies, making them an essential tool in the scientific arsenal.

A Game-Changer in Immune Studies

Nude rats, characterized by their absence of a thymus gland, are devoid of a functioning immune system. This absence results from a genetic mutation affecting the Foxn1 (Forkhead box N1) gene, crucial for thymus development and T cell maturation. Without a properly functioning thymus, nude rats exhibit compromised T cell function, making them immunodeficient compared to their immunocompetent counterparts. This distinctive feature makes them indispensable for investigating various aspects of human diseases, such as autoimmune disorders, infectious diseases, and cancer.

The Role of the Immune System in Disease Pathogenesis

Incomplete Representation

Immunodeficient rats provide an incomplete representation of disease pathogenesis, particularly in diseases where the immune system plays a significant role. While studying diseases in the absence of a robust immune response can yield valuable insights, it may not fully capture the complexity of the disease in humans. Many diseases, including infections and certain cancers, involve intricate interactions between the pathogen or tumor and the immune system. Ignoring these interactions can lead to an oversimplified view of disease progression.

The Immune System’s Protective Role

Lack of Protective Mechanisms

Immunodeficient rats are highly susceptible to infections and lack protective mechanisms against pathogens that a functional immune system would provide. This susceptibility can limit the practicality of studying certain infectious diseases, as the rapid progression of infections in these rats may not accurately represent the course of the disease in humans.

Missed Opportunities for Immunotherapy

In the field of cancer research, immunotherapy has emerged as a promising treatment approach. Immunodeficient rat models may not fully capture the potential benefits of immunotherapies that rely on the host’s immune response to target tumors. Therefore, the use of athymic rats in cancer studies might not reflect the actual therapeutic outcomes achievable in patients with functional immune systems.

Studying Autoimmune Disorders

Autoimmune Disease Modeling

The reduction of T cell activity in athymic nude rats minimizes the host’s immune response when studying diseases, allowing researchers to focus on the disease’s mechanisms without the interference of a robust immune system. However, this is not without concern regarding whether this is translational (you’re studying disease mechanism in a host that may have residual immunity) This is particularly valuable when modeling diseases that involve immune system dysregulation, such as autoimmune disorders. Nude rats provide an excellent platform for simulating autoimmune diseases, allowing researchers to dissect the underlying mechanisms and test potential therapies.

Autoimmune disorders are characterized by the immune system mistakenly attacking the body’s own tissues. Athymic rats, with their compromised T cell function, are ideal for creating experimental models of autoimmune diseases. Researchers can introduce specific autoantigens or induce autoimmune responses in these rats to better understand the underlying mechanisms of autoimmune disorders like lupus, rheumatoid arthritis, and type 1 diabetes.

Infectious Disease Investigations

When studying infectious diseases, it is essential to assess the pathogenesis of the disease in the absence of a strong immune response. Athymic rats serve as valuable hosts for infectious disease research because they lack the functional T cells required for an effective immune response. This enables scientists to study the progression of infections, evaluate potential treatments, and develop diagnostic tools without the confounding influence of an intact immune system.

  • Viral Pathogenesis: Nude rats have played a pivotal role in understanding viral infections like HIV/AIDS, paving the way for antiviral drug development.
  • Tuberculosis Studies: These rats have also been instrumental in studying tuberculosis, contributing to the development of better diagnostic tools and treatments.

List of Humanized Rodent Models

The availability and characterization of immunodeficient rat models is more limited compared to mouse models. Researchers should carefully consider the specific research goals and requirements when selecting an immunodeficient rat model for their studies. Here’s a list of immunodeficient rat models ranked by the level of severity of immunodeficiency, from the least severe to the most severe:

Nude Rats (NU/NU or Foxn1rnu Rats)

  • Nude rats lack a functional thymus, resulting in compromised T cell function.
  • They have a moderate level of immunodeficiency and are often used for xenograft studies.

RNU Rats (Rowett Nude Rats)

  • RNU rats are athymic nude rats with a more severe immunodeficiency than standard nude rats.
  • They lack a thymus gland and have limited T cell function, making them suitable for xenotransplantation and cancer research.

SRG Rats (SIRPA Rag2 IL2Rγnull Rats)

  • SRG rats are highly immunodeficient rats.
  • They lack B, T, and NK cells and have a non-functional IL2 receptor gamma chain, similar to NSG mice.
  • SRG rats are valuable for human tissue engraftment studies and regenerative medicine research.

Here’s a list of immunodeficient mouse models ranked by the level of severity of immunodeficiency, from the least severe to the most severe:

Nude Mice (NU/NU or Foxn1nu Mice)

  • Nude mice lack a functional thymus and have compromised T cell function.
  • They have moderate immunodeficiency and are commonly used for xenograft studies, especially in cancer research.

SCID-Beige Mice (CB17.Cg-Prkdcscid Lystbg-J/Crl)

  • SCID-Beige mice are immunodeficient mice with a mutation in the Lyst gene.
  • They have reduced NK cell function in addition to lacking B and T cells, making them useful for certain immune-related studies.

TK-NOG Mice (NOD.Cg-Prkdcscid Il2rgtm1Sug Tg(CMV-EGFP/TK, – DTR)1Eav/MloySzJ)

  • TK-NOG mice are NOG mice engineered to express the thymidine kinase (TK) gene under a cytomegalovirus (CMV) promoter.
  • This model allows for selective depletion of human cells by ganciclovir treatment.
  • TK-NOG mice are useful for studying immune cell function and the effects of targeted cell depletion.

Hu-PBL-SCID Mice (Human Peripheral Blood Lymphocyte-SCID Mice)

  • Hu-PBL-SCID mice are immunodeficient mice engrafted with human peripheral blood lymphocytes.
  • They are used to study human immune responses, graft-versus-host disease (GVHD), and immunotherapies.

Mice LT (Bone Marrow, Liver, Thymus Mice)

  • LT mice are created by transplantation of human fetal liver and thymus tissues into immunodeficient mice, such as NOD-SCID or NSG mice.
  • These mice enable the development of a human immune system, offering a unique model for immune-related research.

NOG (NOD-SCID IL2Rγnull) Mice

  • NOG mice lack B, T, and NK cells and have a non-functional IL2 receptor gamma chain.
  • They support a wide range of human cell engraftments and are widely used for humanization studies.

Rag2 Knockout Mice

  • Rag2 knockout mice lack mature B and T lymphocytes due to a deficiency in the Rag2 gene.
  • They are useful for studying immune development and transplantation.

BRG (BALB/c Rag2 IL2Rγnull) Mice

  • BRG mice lack B, T, and NK cells and have a non-functional IL2 receptor gamma chain.
  • They are valuable for human cell engraftments and xenograft studies.

NBSGW (NOD-Prkdcscid IL2Rγnull) Mice

  • NBSGW mice combine multiple immunodeficient mutations, resulting in a highly immunodeficient model.
  • They lack B, T, and NK cells and are used for humanization studies and transplantation.

ISTRG Mice (MITRG, NSG-HLA-A2/HHD, or MISTRG/A2)

  • ISTRG mice lack B, T, and NK cells and have a non-functional IL2 receptor gamma chain.
  • They allow for robust engraftment of human hematopoietic stem cells, immune cells, and tissues.
  • ISTRG mice are widely used for the study of human immune responses, cancer, and infectious diseases.

SCID (Severe Combined Immunodeficiency) Mice

  • SCID mice lack functional B and T lymphocytes, resulting in a severe combined immunodeficiency.
  • Highly susceptible to infections
  • widely used for engraftment studies

Please note that the choice of an immunodeficient mouse model should be based on the specific research goals and requirements, as each model offers unique advantages and limitations for different applications in biomedical research.

Creating Experimental Models Using Nude Rats for Preclinical Studies

Advancing Drug Testing and Development

Nude rats’ suitability as preclinical models has revolutionized pharmaceutical research by offering a closer approximation of human responses to drugs and therapies.

Drug Efficacy Testing

Cancer Drug Screening: Nude rats with implanted human tumors serve as prime candidates for assessing the efficacy of potential cancer treatments.

Pharmacokinetics Studies: These rats enable researchers to assess drug absorption, distribution, metabolism, and excretion (ADME), crucial for drug development.

Toxicity Assessments & Dose Optimization

Nude rats assist in evaluating drug toxicity/drug safety, reducing the risk of adverse effects in clinical trials. Taking things a step further by conducting dose-response studies, researchers can determine optimal drug dosages for minimal side effects.

Comparative Analysis of Athymic Nude Rat Models and Athymic Nude Mouse Models in Immuno-Oncology Research

Tumor Xenografts

Athymic rats are extensively used in cancer research, particularly in the creation of xenograft models. These models involve the implantation of human cancer cells or tissues into athymic rats. Since these rats have compromised T cell-mediated rejection mechanisms, they allow for the growth and study of human cancer cells without immune rejection. This facilitates the investigation of tumor biology, tumor progression, and the testing of novel cancer therapies. Athymic rat xenograft models are crucial for assessing the efficacy of potential cancer treatments. Nude rats often exhibit superior tumor growth, making them ideal for oncology research. The larger size of these rats also allows for more extended experimental durations, critical for studying tumor progression.

Immune Response Studies

While athymic rats lack an adaptive immune response, their innate immune system remains intact. This allows researchers to focus on the role of innate immunity and other components of the immune system in various disease processes. Studying immune responses in athymic rats provides insights into the interaction between the innate immune system and diseases, which can be valuable for developing immunotherapies and treatments. Nude rats’ longer lifespan enables the observation of chronic immune responses, making them preferable for extended immunology investigations. Efforts to humanize the immune system in nude rats hold great promise for personalized medicine research.

Advancing Personalized Medicine Research with Nude Rat Cancer Models

Tailoring Treatments to Individuals

Personalized medicine relies on understanding individual variations in disease susceptibility and drug responses, and nude rat cancer models are integral to this endeavor. As an example, nude rats are instrumental in developing patient-derived xenografts (PDX), allowing for customized cancer treatment strategies. PDX models in nude rats facilitate the evaluation of drug responses unique to individual patients.

Exploring the Role of RNU Rats and SRG Rats in Immunology and Transplantation Studies

In the quest to expand the capabilities of nude rats, specialized strains like RNU and SRG rats have been developed.

RNU Rats

RNU rats exhibit a higher degree of immunodeficiency, making them exceptionally suitable for transplantation and engraftment studies. These rats are pivotal in studying tumor biology and evaluating novel cancer therapies.

SRG Rats

SRG rats, with their enhanced tissue regeneration capabilities, are crucial for regenerative medicine and transplantation research. Their unique characteristics allow for better engraftment of human tissues and organs.

The Significance of Nude Rats in Studying Immune Responses and Tumor Biology

Nude rats have provided vital insights into immune responses and tumor biology, driving advancements in both fields. Nude rats have elucidated the intricate interactions between tumors and their microenvironment, aiding in the development of targeted therapies. Their contribution to angiogenesis research has implications for cancer treatment and tissue engineering.

Final Thoughts on Immunodeficient Rats in Preclinical Studies

The immunodeficient nature, adaptability, and unique variants like RNU and SRG rats have propelled our understanding of human diseases, drug development, personalized medicine, and regenerative therapies. As scientists continue to unlock their potential, these remarkable models promise to lead us toward groundbreaking discoveries and innovative treatments, ultimately improving human health and well-being.

References

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  2. Song, C. W., Glatstein, E., Marks, L. B., Emami, B., Grimm, J., Sperduto, P. W., Kim, M. S., Hui, S., Dusenbery, K. E., & Cho, L. C. (2021). Biological Principles of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiation Surgery (SRS): Indirect Cell Death. International journal of radiation oncology, biology, physics, 110(1), 21–34. https://doi.org/10.1016/j.ijrobp.2019.02.047.
  3. Chen, J., Liao, S., Xiao, Z., Pan, Q., Wang, X., Shen, K., Wang, S., Yang, L., Guo, F., Liu, H. F., & Pan, Q. (2022). The development and improvement of immunodeficient mice and humanized immune system mouse models. Frontiers in immunology, 13, 1007579. https://doi.org/10.3389/fimmu.2022.1007579.
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